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Calcium metabolism handout

This document discusses calcium homeostasis and disorders, including hypercalcemia and hyperparathyroidism. It provides details on the roles of parathyroid hormone (PTH), vitamin D, and calcitonin in regulating calcium levels. It examines causes of hypercalcemia such as primary hyperparathyroidism, malignancy, and vitamin D toxicity. Guidelines for treatment of asymptomatic primary hyperparathyroidism with surgery or medication are reviewed based on calcium levels, bone mineral density, kidney stones, and age. Non-surgical treatments including vitamin D supplementation and cinacalcet are also discussed.

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Calcium disorders Roderick Warren Registrar teaching Buckfastleigh, July 2014
Calcium homeostasis Please see the handout (assuming I remembered it)
Vitamin D from skin and diet 25-hydroxylase 25(OH)-D – inactive (?) 1-OHase PTH effects on the kidney 1.Stimulates activation of vit D. 2.Promotes phosphate excretion. 3.Reduces calcium resorption. 1,25(OH)2-D effects on kidney Increases Ca resorption 1α-hydroxylation Stimulated by Inhibited by PTH 1,25(OH)2-D Low PO4 High PO4 PTH effect on bone Calcium export PTH production Main stimulus is low Ca2+. Inhibited by 1,25(OH)2-D. Mg required. Calcitonin production Main stimulus high Ca2+ (ionized>1.15) – also glucagon, gastrin, ß-adrenergic agonists (?reason for low Ca in acute illness) Calcitonin effects on bone • inhibits osteoclast resorption • thereby lowers Ca and PO4 • no effect on Mg 1,25(OH)2-D effects on gut Increases Ca2+ and PO4 absorption Vit D direct effect on bone? Unclear Parathyroid hormone Calcitonin 1,25-OH2-D
Hypercalcaemia
Question Sue has this: • Calcium 3.4 mmol/L • PTH 0.6 pmol/l (1.6-6.9) What are the differential diagnoses?
Answer Sue has this: • Calcium 3.4 mmol/L • PTH 0.6 pmol/l (1.6-6.9) Diagnosis could include: • Cancer • Vit D poisoning • Granulomatous disease etc
Causes of hypercalcaemia Malignancy 90% of Primary hyperparathyroidism all cases Other causes Familial Drugs: lithium, thiazides, activated vitamin D Granulomatous diseases: sarcoid etc Milk alkali syndrome Hyperthyroidism Prolonged immobilisation
Malignancy causing hypercalcaemia Cancer site Mechanism Lung PTH-rp (80%) Breast Bony mets (20%) Haematological e.g. myeloma Head and neck Renal Prostate Unknown GI
PTH-related peptide Fetal equivalent of PTH Maintains fetal sCa slightly higher than maternal Activates PTH receptor Typical pattern is - high calcium - low phosphate High phosphate suggests non PTH/PTHrp cause
Is this hypercalcaemia due to cancer? Low PTH - Cancer until proven otherwise: - Serum electrophoresis, Bence Jones - Tumour markers (PSA etc) - CT TAP - Bone scan - Endoscopy Normal or high PTH - Almost certainly not cancer - rarely tumours co-secrete PTH and PTH-rp - parathyroid carcinoma
Question Bob has this: • Calcium 2.9 mmol/L • Phosphate 2.4 mmol/L • PTH 42 pmol/l (1.6-6.9) What are the differential diagnoses?
Answer Bob has this: • Calcium 2.9 mmol/L • Phosphate 2.4 mmol/L • PTH 42 pmol/l (1.6-6.9) Diagnosis could include: • CKD with tertiary hyperparathyroidism
Hyperparathyroidism Primary Secondary Parathyroid adenoma Renal failure Impaired PO4 excretion High PTH Impaired Vit D activation High calcium High PTH Low phosphate Normal or high phosphate Normal or low calcium
Hyperparathyroidism Primary Secondary Parathyroid adenoma Renal failure Impaired PO4 excretion High PTH Impaired Vit D activation High calcium High PTH Low phosphate Normal or high phosphate Normal or low calcium
Vitamin D from skin and diet 25-hydroxylase 25(OH)-D – inactive (?) 1-OHase PTH effects on the kidney 1.Stimulates activation of vit D. 2.Promotes phosphate excretion. 3.Reduces calcium resorption. 1,25(OH)2-D effects on kidney Increases Ca resorption 1α-hydroxylation Stimulated by Inhibited by PTH 1,25(OH)2-D Low PO4 High PO4 PTH effect on bone Calcium export PTH production Main stimulus is low Ca2+. Inhibited by 1,25(OH)2-D. Mg required. Calcitonin production Main stimulus high Ca2+ (ionized>1.15) – also glucagon, gastrin, ß-adrenergic agonists (?reason for low Ca in acute illness) Calcitonin effects on bone • inhibits osteoclast resorption • thereby lowers Ca and PO4 • no effect on Mg 1,25(OH)2-D effects on gut Increases Ca2+ and PO4 absorption Vit D direct effect on bone? Unclear Parathyroid hormone Calcitonin 1,25-OH2-D
1y hyperparathyroidism - epidemiology Age Increases with age 90% aged over 50 Gender Female preponderance 70-80%
1y hyperparathyroidism - epidemiology Prevalence Increasing Tayside 6 per 1000 population. About 20 per 1000 in women age >50. (Defined as Ca>2.55). Mirrors increased calcium testing. (Calcium testing increased from 5% to 15% of population each year). California About 4 per 1000 in older women (Defined as Ca>2.6.) Yu et al, Clin Endo 2009, 71, 485-493. Yeh et al, JCEM 2013, 98, 1122-1129.
1y hyperparathyroidism - epidemiology How common is it really? In older women – 0.5 to 2% prevalence Based on 15% of population having blood tests What would it be if 100% of population were tested?
1y hyperparathyroidism - diagnosis Elevated calcium Elevated or non-low PTH Not secondary to renal failure High phosphate eGFR<60
Question Mary has this: • Calcium 2.75 mmol/L • PTH 18.2 pmol/L What are the differential diagnoses?
Answer Mary has this: • Calcium 2.75 mmol/L • PTH 8.2 pmol/L • Vitamin D 15 nmol/L Diagnosis could include: • Primary hyperparathyroidism with vit D deficiency • Familial hypercalcaemia with vit D deficiency
1y hyperparathyroidism - diagnosis Elevated calcium Elevated or non-low PTH Not secondary to renal failure High phosphate eGFR<60 Not due to drugs Thiazides Lithium Not due to vitamin D deficiency
Effect of vitamin D on PTH Vitamin D insufficiency causes secondary hyperparathyroidism PTH on Y-axis is approx 2- 11 pmol/L Vit D on X-axis is approx 0 to >75 nmol/L
Vitamin D from skin and diet 25-hydroxylase 25(OH)-D – inactive (?) 1-OHase PTH effects on the kidney 1.Stimulates activation of vit D. 2.Promotes phosphate excretion. 3.Reduces calcium resorption. 1,25(OH)2-D effects on kidney Increases Ca resorption 1α-hydroxylation Stimulated by Inhibited by PTH 1,25(OH)2-D Low PO4 High PO4 PTH effect on bone Calcium export PTH production Main stimulus is low Ca2+. Inhibited by 1,25(OH)2-D. Mg required. Calcitonin production Main stimulus high Ca2+ (ionized>1.15) – also glucagon, gastrin, ß-adrenergic agonists (?reason for low Ca in acute illness) Calcitonin effects on bone • inhibits osteoclast resorption • thereby lowers Ca and PO4 • no effect on Mg 1,25(OH)2-D effects on gut Increases Ca2+ and PO4 absorption Vit D direct effect on bone? Unclear Parathyroid hormone Calcitonin 1,25-OH2-D
How could vitamin D deficiency be relevant in a hypercalcaemic patient? Theoretically (and, very occasionally, for real): • PTH is too high for FHH • Vit D replacement lowers PTH • PTH now plausible for FHH
Is vitamin D replacement safe in primary hyperparathyroidism? Wagner Das Tucci Grey N 35 16 56 21 Vit D baseline 36 29 36.4 28 Vit D final 105 71.8 88.6 77 Calcium baseline 2.69 2.75 2.74 2.70 Calcium final 2.60 2.65 2.73 2.69 PTH baseline Unchanged 18.6 15.3 12.4 PTH final 18.0 14.1 9.2 Problem patients None None None None Wagner Endocr Pract 2013, 19(3), 420-5. Das, Endocr Abstr 2014, 34, P6. Tucci EJE 2009, 161, 189. Grey, JCEM 2005 90(4) 2122. Local anecdotal reports of hypercalcaemia. Could this be due to natural variation? CV around 4% i.e. not unusual to see +/- 0.2 mmol/L.
Parathyroid bone disease Osteoporosis • Decreased BMD in PHPT patients • Rate of bone less similar to normal population Fracture • 1.5-fold increase in all fractures PHPT • 3-fold vertebra • 2-fold forearm • 1.5-fold hip
Parathyroid bone disease Left – sub-periosteal erosions Above – bands of osteosclerosis “rugby jersey” appearance Right – above, metaphyseal erosion in adolescence, and below, after vit D treatment Cundy, Ulst Med J 1985, 54, S34-43
Brown tumours Osteitis fibrosa cystica Wikipedia
Primary hyperparathyroidism Investigations Bloods Calcium (high). Phosphate (low or low-normal). PTH (high or normal). Liver (alk phos often high but not diagnostic). Vitamin D (usually low and very occasionally confounds diagnosis). Urine 24-hour urine calcium indices (see later). Renal USS Only in patients with history suggestive of stones. DEXA May influence surgery, or prompt bisphosphonate treatment.
Question Jemima has this: • Age 79 • No symptoms • Calcium 2.71 mmol/L • PTH 7.2 pmol/L • Vit D 50 nmol/L • 24-hr urine Ca 6.8 mmol • eGFR 51 • DEXA T -2.7 Z -0.2 at spine What treatment?
Answer Jemima has this: What treatment? • Age 79 Looks like PHPT • No symptoms Osteoporosis • Calcium 2.71 mmol/L • PTH 7.2 pmol/L • Vit D 50 nmol/L Really not keen on surgery • 24-hr urine Ca 6.8 mmol “Why do I need an op doc?” • eGFR 51 • DEXA T -2.7 Z -0.2 at spine
Primary hyperparathyroidism Guidelines - when to operate Serum calcium > 2.80 mmol/L (Actually >0.25 mmol/L above reference range). Osteoporosis BMD T-score <-2.5 at any site, or previous fragility fracture. Renal stones Age <50 Bilzekian et al, J Clin Endo Metab 2009, 94, 335-339.
Primary hyperparathyroidism Reasons to operate Symptoms Nausea. Thirst. Fatigue. Aches. Constipation. Progressive hypercalcaemia Risk of future symptoms or hospital admission. Osteoporosis Renal stones Cardiovascular disease??
Primary hyperparathyroidism Reasons not to operate Symptoms Vague. Conflicting evidence of benefit. Progressive hypercalcaemia Rare in prospective studies - less than 5%. Osteoporosis Often criteria met solely due to age. No proof of fracture reduction. Similar BMD benefit to bisphosphonates. Estimated absolute benefit is low - around 1:100 or less Too much medicine? Prevalence tripled in 10 years as a result of more blood tests.
Primary hyperparathyroidism Non-surgical treatments Vitamin D Not evidenced, sounds plausible. Bisphosphonates Good evidence for # prevention though not tested in PHPT. Can lower sCa slightly – would not use for this purpose. Cinacalcet Now licensed for PHPT where parathyroidectomy is inappropriate Cost £125-350 per month Lowers sCa by 0.25-0.3 mmol/L (perhaps more in more severe cases) No benefit on BMD demonstrated
Surgery for “asymptomatic” hyperparathyroidism - 1 Location Sweden, Norway, Denmark. Subjects 191 patients with PHPT No parathyroid bone disease Calcium 2.6-2.85 No previous neck surgery Age 50-80 No renal impairment (creat>130) No interfering meds (thiazides etc) No kidney stones No MEN/familial hypercalcaemia No psych disorders Intervention Surgery or observation Follow-up 2 years Bollerslev et al, J Clin Endo Metab 2007, 92, 1687-1692.
Outcomes Bollerslev et al, J Clin Endo Metab 2007, 92, 1687-1692. Surgery Observation N 96 95 Age 64 64 Female/male 83/13 82/13 Baseline calcium 2.70 2.69 Calcium change -0.30 -0.02 Baseline creatinine 82 81 Final creatinine 0 0 BMD lumbar 1.09 1.06 BMD change +0.04 -0.04 Fractures Not reported
Outcomes Physical component of SF36 – fell in both groups, no difference between groups. Mental component of SF36 – fell in both groups, no difference between groups.
Surgery for “asymptomatic” hyperparathyroidism - 2 Ambrogini et al, J Clin Endo Metab 2007, 92, 1687-1692. Location Italy. Subjects 50 patients with PHPT No parathyroid bone disease Calcium 2.55-2.8 No kidney stones 24-hr urine calcium<10mmol No osteoporosis Age 50-75 No neck surgery No recent menopause No MEN/familial hypercalcaemia No major renal impairment Intervention Follow-up Surgery or observation 1 year
Outcomes Bollerslev et al, J Clin Endo Metab 2007, 92, 1687-1692. Surgery Observation N 24 26 Age 64 65 Female/male 22/2 24/2 Baseline calcium 2.55 2.55 Calcium change “Normalised” +0.05 Baseline creatinine clearance 93 93 Final creatinine clearance “Stable” 98 BMD lumbar 0.85 0.83 BMD change +4% -1% Fractures Not reported
Outcomes Solid line – surgery Dashed line - observation
Natural history of untreated PHPT No really good long-term studies. Surgery vs observation trials (as before) Bollerslev (Swedish study) - tiny drop -0.02 over 2 years Ambrogini (Italian study) - small rise +0.05 over 1 year
Natural history of untreated PHPT PEARS study – parathyroid epidemiology and audit research study, Dundee Records linkage – lab data to hospital records Definition of PHPT • Serum calcium >2.55 x 2 with PTH>3 (ref 1-6.9) • Serum calcium >2.55 x 1 with PTH>6.9 Definition of progression • Serum calcium 2.90 • Serum calcium rise of 0.2 mmol/L Yu et al, Q J Med 2011, 104, 513-521.
Natural history of untreated PHPT Mean calcium clearly fell Individual progression • 13% of total showed any. • 1% of total showed sustained progression. Possible problems • Was it really hyperpara? • Does it apply to more severe hyperpara? Yu et al, Q J Med 2011, 104, 513-521.
Osteoporosis http://www.iofbonehealth.org/epidemiology. http://www.cdc.gov/nchs/data/nhanes/databriefs/osteoporosis.pdf . Both accessed 27th June 2014. Prevalence increases with age • 30% of post-menopausal women in Europe have osteoporosis. • 87% of US women aged over 80 have osteopenia or osteoporosis
Fracture reduction No RCT evidence for fracture reduction Retrospective studies • Fewer fractures in surgically- versus medically-treated • But obvious confounders Non-surgically treated were older and frailer What about BMD? • RCT evidence shows 5-8% benefit after surgery • What does that mean?
Fracture risk estimation No RCT evidence for fracture reduction Retrospective studies • Fewer fractures in surgically- versus medically-treated • But obvious confounders Non-surgically treated were older and frailer What about BMD? • RCT evidence shows 5-8% benefit after surgery • What does that mean?
Primary hyperparathyroidism Reasons not to treat Symptoms Vague. Conflicting evidence of benefit. Progressive hypercalcaemia Rare. Osteoporosis Criteria met solely due to age. No proof of fracture reduction. Similar BMD benefit to bisphosphonates. Estimated benefit is low - around 1% absolute risk reduction. Too much medicine? Prevalence tripled in 10 years as a result of more blood tests. What treatment?
Primary hyperparathyroidism Investigations Bloods Calcium (high). Phosphate (low or low-normal). PTH (high or normal). Liver (alk phos often high but not diagnostic). Vitamin D (usually low and very occasionally confounds diagnosis). Urine 24-hour urine calcium indices (see later). Renal USS Only in patients with history suggestive of stones. DEXA May influence surgery, or prompt bisphosphonate treatment.
Question Roberta has this: Treatment: • Age 69 Keen to have surgery • Polyuria, fatigue, aches No contra-indications • Calcium 2.81 mmol/L • PTH 7.2 pmol/L SestaMIBI scan: • Vit D 50 nmol/L No apparent adenoma • 24-hr urine Ca 6.8 mmol • eGFR 51 What next? • DEXA T -2.7 Z -0.2 at spine
Answer Roberta has this: Treatment: • Age 69 Keen to have surgery • Polyuria, fatigue, aches No contra-indications • Calcium 2.81 mmol/L • PTH 7.2 pmol/L SestaMIBI scan: • Vit D 50 nmol/L No apparent adenoma • 24-hr urine Ca 6.8 mmol • eGFR 51 What next? • DEXA T -2.7 Z -0.2 at spine Operate Or further localisation studies
Primary hyperparathyroidism Localisation studies What is the aim? • Exclude retrosternal/ectopic adenoma • Identify solitary parathyroid adenoma vs multiple adenomata vs hyperplasia • Least possible surgery
Primary hyperparathyroidism Localisation studies Conventional (Kochers) incision • Originally 8-10cm • Eventually reduced to 4-6cm Minimal access • Arbitrary definition • E.g. below 2.5cm
Primary hyperparathyroidism MIBI scan Theoretically: • 90% sensitivity, 98% specificity • 87% are solitary adenomas • 9% hyperplasia • 3% multiple adenomas • <1% cancer • Therefore, 78% of patients (90% of 87%) are candidates for unilateral neck exploration Reality: • Often do not localise • Equipment dependent • Affected by MNG
Parathyroid surgery Exeter Parathyroid SestaMIBI Lateralising With no pointers to secondary hyperpara Not lateralising (appropriate PTH, PO4, eGFR) Or possibility of secondary hyperpara Unilateral neck exploration Examination of both parathyroids Bilateral exploration One abnormal Both abnormal Remove and close
Primary hyperparathyroidism Other localisation studies Ultrasound Sesta-MIBI - SPECT/CT Parathyroid venous sampling Minimally-invasive radioguided parathyroidectomy (MIRP) (MIBI injection, Geiger counter to find active parathyroids) Intra-operative PTH
Post-op hypocalcaemia Frequency • About 10-30% of cases • More likely with… severe hypercalcaemia vitamin D deficiency very high PTH multi-gland surgery Prevention • Vitamin D repletion • Cinacalcet? • Bisphosphonates?
Post-op hypocalcaemia Post-operative monitoring Check corrected calcium 1st post-op day Ca >2.2 Ca 2.0 – 2.19 and/or more than 0.2 mmol/l lower than pre-op Ca 1.7 – 1.99 * Ca <1.7 *or markedly symptomatic Low risk group Repeat Ca day 7 High risk group Repeat day 3-4 and day 7 Start or Continue pre-op Adcal D3 Repeat in 2 days Start 1alpha calcidol 1mcg od and Sandocal 1000 bd Give iv calcium gluconate 10ml. Repeat serum calcium after 6 hours. Commence 1 alpha calcidol 2 mcg od and Sandocal 1000 bd Ca 2.0 – 2.19 Repeat after 3 days If Ca >2.0 repeat day 7 Review 6 weeks by Endocrinology service Ca 1.7 – 1.99 Increase 1 alpha to 2mcg od. Repeat daily until Ca >2.0 Ca >2.2 Rob Dyer – draft, 2012.
Question Jake has this: What investigations? • Age 39 • Polyuria, fatigue, aches • Calcium 2.85 mmol/L • PTH 78.2 pmol/L • Vit D 52 nmol/L • 24-hr urine Ca 6.8 mmol • eGFR >90 • DEXA T -0.4 • Surgery shows four-gland hyperplasia
Answer Jake has this: What investigations? • Age 39 • Polyuria, fatigue, aches MEN guidelines 2012 • Calcium 2.85 mmol/L 2+ MEN-associated tumours • PTH 78.2 pmol/L 1st deg rel of known MEN1 • Vit D 52 nmol/L Parathyroid adenomas <30 • 24-hr urine Ca 6.8 mmol Multigland parathyroid disease • eGFR >90 Gastinoma • DEXA T -0.4 Pancreatic NET • Surgery shows four- gland hyperplasia
Prevalence of MEN in hyperparathyroidism High penetrance (95%+) of PHPT in known MEN by age 50 • Often said no need to consider MEN if diagnosed over 50 But would PHPT be diagnosed before 50 if MEN not known? • E.g. develops age 45, diagnosed age 55? Prevalence of MEN in PHPT • Uchino et al – 25% menin mutations • Yip et al – 4% prevalence but 26% if hyperplasia • De Laat et al – 7% prevalence Always ask about FH of hypercalcaemia, renal stones, brain tumours, neck surgery, ulcers, pancreatic tumours
Primary vs secondary vs tertiary hyperparathyroidism Divide calcium by 4 to get mmol/L DividePTHbyabout10togetpmol/L
Primary Secondary Parathyroid adenoma Renal failure Impaired PO4 excretion High PTH Impaired Vit D activation High calcium High PTH Low phosphate Normal or high phosphate Normal or low calcium Secondary hyperparathyroidism
Secondary hyperparathyroidism High or normal phosphate Low or normal calcium High PTH eGFR below 60 Levin–AmJKidDis1991,34,125-134.
NICE 2008 guidelines • Monitor in CKD 4/5 (e.g. in diabetes clinics) • Measure Ca, PO4, PTH • Decide frequency of monitoring by results and clinical circumstances. Seek specialist opinion. (Just do it annually?). • Cholecalciferol or ergocalciferol for CKD 1-3b • Alfacalcidol or calcitriol for CKD 4-5 Secondary hyperparathyroidism management
AKA refractory secondary hyperparathyroidism • Development of autonomous nodular parathyroid hyperplasia • Hypercalcaemia Indications for surgery • Severe hypercalcaemia/hyperphosphataemia • Parathyroid bone disease • Extraskeletal calcification • Unexplained symptomatic myopathy • WITH PTH>800 pg/mL (88 pmol/L) (all of the above can develop in dialysis patients for other reasons, so must confirm presence of hyperparathyroidism) “Tertiary” hyperparathyroidism
Surgical options – no agreement which is best • Total parathyroidectomy (unpopular) • Total parathyroidectomy with auto-transplantation into forearm Theoretically – if recurrent, no need for re-exploration of neck. But persistent hypercalcaemia after removal of arm graft is quite common, i.e. it was in the neck all along. • Subtotal parathyroidectomy (leaving 40-60mg of the least hyperplastic gland) “Tertiary” hyperparathyroidism
Persistent hyperparathyroidism • Nodular hyperplasia from prolonged secondary hyperpara Normal renal function • Eliminates resistance to PTH due to uraemia • Restores normal 1-hydroxylation of vit D Hypercalcaemia after renal transplant
Causes of hypercalcaemia Malignancy 90% of Primary hyperparathyroidism all cases Other causes Familial Drugs: lithium, thiazides, activated vitamin D Granulomatous diseases: sarcoid etc Milk alkali syndrome Hyperthyroidism Prolonged immobilisation
Familial benign (hypocalciuric) hypercalcaemia CaSR mutation • Body “sees” a high calcium level as normal • Present from birth • One explanation for failed parathyroid surgery Misnamed • Normocalciuric (just lower than expected) In most cases: • PTH not very high • Urine calcium not elevated • Calcium:creatinine clearance ratio <0.02 • No osteoporosis • Asymptomatic
Familial (benign) (hypocalciuric) hypercalcaemia PHPT FBHH PTH pmol/L 50% above 8-9 50% below 3 95% below 8.5 99% below 9.1 24-hr urine calcium mmol 70% above 6.5 50% below 2.3 95% below 6.5 99% below 9.0 Calcium:creatinine clearance ratio 98% below 0.02 65% above 0.02 95% above 0.06 Gunn et al Ann Clin Biochem 2004, 41, 441-458 Christensen et al Clin Endo 2008, 69, 713-720. CCCR>0.02 excludes FHH. Consider genetic testing if <0.02 (NB only 70% of familial cases are positive on genetic tests).
Familial benign (hypocalciuric) hypercalcaemia Severe cases are reported • Homozygous mutations • Severe symptomatic hypercalcaemia • Osteoporosis • Very high PTH
Parathyroid jaw tumour syndrome • Rare • Autosomal dominant • Parathyroid tumours ~15% carcinomas • Fibro-osseous tumours of jaw bones • Plus loads of other tumours – Wilm’s, renal cysts, renal hamartomas, renal cortical adenomas, papillary renal cell carcinomas, pancreatic adenocarcinomas, testicular seminomas, uterine.
Lithium Causes hyperparathyroidism Expect PTH to be elevated. If low PTH - look for cancer. Also causes diabetes insipidus Severe hypercalcaemia causes dehydration. DI causes dehydration. Dehydration worsens hypercalcaemia. Nightmare combo Mania with severe hypercalcaemia and renal impairment.
Lithium – prevalence of hypercalcaemia Lally et al 5% of 33 patients Twigt et al 15.6% of 314 patients Duration of Li therapy was main predictor No hypercalcaemia in control group of non-Li psych patients Bendz et al 6% incidence in 142 patients over 19 years 13 consented to trial of Li withdrawal – all ineffective Ir Med J 2013 106 15-17. Int J Bipolar Dis 2013 1 18. J Int Med 1996 240 357-365.
Lithium – management of hyperparathyroidism Surgery Adenoma vs hyperplasia Withdrawal of lithium Mainly ineffective (short-term studies only) But worth a try
Thiazides Effects ● Small increase (1-2%) in serum total calcium ● Small increase (10-20%) in PTH ● Little or no effect on ionized calcium ● Reduction in urinary calcium excretion Does it matter? ● Probably not ● Most cases of hypercalcaemia with thiazides turn out to be coincidental primary hyperparathyroidism Rejnmark et al. Euro J Clin Invest 2003, 33, 41-50. Wermers et al, Am J Med 2007, 120, 911.
Thiazides and hypercalcaemia – practical points Stop the thiazide ● Recheck calcium and PTH ● Is there malignancy? ● Is there primary hyperparathyroidism? Could restart it if all OK ● E.g. if mild primary hyperpara for “watch and wait”
No cause found. What next? Hypercalcaemia Low or non-elevated PTH No evidence of malignancy No lithium No thiazides No calcium/vit D supplements Normal thyroid function
Rarer stuff Granulomatous diseases: sarcoid etc CT chest. s-ACE?? Milk alkali syndrome Prolonged immobilisation Cirrhosis I don’t know the mechanism Adrenal insufficiency I don’t know the mechanism Primary or secondary
Acute management of hypercalcaemia When is admission required? • Definitely if sCa>3.5 mmol/L • 3-3.5 mmol/L – depends on trend, age, frailty, renal function etc
Acute management of hypercalcaemia 1. Hydration • 4-6 litres 0.9% saline over 24 hours • Loop diuretics for fluid overload – not effective at lowering calcium 2. IV bisphosphonate • Zoledronate 4mg • Pamidronate 30-90mg 3. Alternatives • Prednisolone 40mg (inhibits 1,25-D production – useful in granuloma, lymphoma, 25-D intoxication) • Cinacalcet • Calcitonin Society for Endocrinology 2013 guideline
Hypocalcaemia
Causes of hypocalcaemia EDTA contamination Low magnesium Respiratory alkalosis PPI Vit D deficiency Hypoparathyroidism - primary - post-surgical - pseudo
EDTA contamination EDTA leakage into biochem tube causes... High potassium Low calcium, magnesium, alk phos Fill biochem tubes before haematology tubes
Hypocalcaemia due to hypomagnesaemia Low magnesium is common in… ● elderly ● diarrhoea ● diuretics ● patients taking PPIs Treatment ● stop diuretics ● stop PPIs ● oral magnesium supplements (limited efficicacy) ○ Maalox or Mucogel - 35 mL/day in divided doses ○ magnesium glycerophosphate - 4 tabs per day ● IV replacement
What level of hypomagnesaemia requires treatment? When you write a guideline, it always ends up more cautious than your real practice ● Many guidelines say Mg<0.5 mmol/L requires urgent IV treatment My comments ● Hypomagnesaemia seems common in general medical patients ● It definitely is common in frail elderly ● In 169 long-term geriatric care patients, 53% had sMg<0.45 mmol/L, 18% had sMg<0.35 mmol/L ● I would treat principally if symptomatic or hypocalcaemic or hypokalaemic Alinzon et al, Arch Geront Ger 2010, 51, 36-40.
Hypocalcaemia due to alkalosis Normal ● albumen carries negative charge ● some albumen is bound to positive H+ ● some Ca2+ is bound to remaining albumen ● free/ionized Ca2+ is biologically active Hyperventilation ● respiratory alkalosis due to blowing off CO2 ● lower H+ concentration ● more negative charged albumen free to bind Ca2+ ● free/ionized Ca2+ falls ● total sCa does not change
When should we measure ionized calcium? Ideally – always In the real world ● if you have a calcium abnormality but struggling to make a diagnosis ● if symptoms suggest hypocalcaemia but normal total sCa
Hypocalcaemia due to vitamin D deficiency Seen in… ● malnutrition ● elderly ● institutionalised ● coeliac / malabsorption / short bowel Treatment ● see formulary ● Adcal D3 or Calcichew D3 (400 units per tab) ● Fultium D3 (800 units per tab) ● OTC - at least 2000 units per day, 8p per day from H&B
Oral: Hypocalcaemia is rare, well under 0.5% Usually occurs after a few weeks Transient IV high dose: Hypocalcaemia more common but still rare Most cases have other risk factors: + coeliac disease + hypoparathyroidism Hypocalcaemia due to bisphosphonates
Gain of function CaSR mutation • Consider if diagnosed young, and never had normal calcium • Family history helpful. (NB affected relatives likely undiagnosed). No simple characterisation • Earliest reported cases had marked hypocalcaemia, low PTH and clearly elevated CCCR. (Perhaps that’s why they were identified). • Confirmed familial cases with no symptoms and normal CCCR. • Treat if symptomatic e.g. seizures • Many case reports of calcification of skull, brain, kidney, cataract • Treatment will increase calcium throughput Familial (hypercalciuric) hypocalcaemia
Question Bill has this: • Calcium 1.4 mmol/L • PTH 76 pmol/l (1.6-6.9) What is the diagnosis?
Answer Bill has this: • Calcium 1.4 mmol/L • PTH 76 pmol/l (1.6-6.9) Diagnosis could include: • Vitamin D deficiency • Renal failure • Rhabdomyolysis • Pseudohypoparathyroidism • etc
Hypoparathyroidism Causes • Usually post-surgical • Rarely, primary or pseudo Features • Low calcium • High phosphate • High PTH • Vitamin D replete • Normal renal function
Vitamin D from skin and diet 25-hydroxylase 25(OH)-D – inactive (?) 1-OHase PTH effects on the kidney 1.Stimulates activation of vit D. 2.Promotes phosphate excretion. 3.Reduces calcium resorption. 1,25(OH)2-D effects on kidney Increases Ca resorption 1α-hydroxylation Stimulated by Inhibited by PTH 1,25(OH)2-D Low PO4 High PO4 PTH effect on bone Calcium export PTH production Main stimulus is low Ca2+. Inhibited by 1,25(OH)2-D. Mg required. Calcitonin production Main stimulus high Ca2+ (ionized>1.15) – also glucagon, gastrin, ß-adrenergic agonists (?reason for low Ca in acute illness) Calcitonin effects on bone • inhibits osteoclast resorption • thereby lowers Ca and PO4 • no effect on Mg 1,25(OH)2-D effects on gut Increases Ca2+ and PO4 absorption Vit D direct effect on bone? Unclear Parathyroid hormone Calcitonin 1,25-OH2-D
Hypoparathyroidism Lack of PTH • Kidneys don’t retain calcium • Kidneys don’t excrete phosphate Activated vitamin D treatment • Increase calcium absorption from gut • Increase phosphate absorption from gut Overall effect • Forced intestinal calcium absorption • Increased renal calcium throughput • High calcium x phosphate product • Nephrocalcinosis (and other calcifcation)
Hypoparathyroidism Treatment targets • sCa around lower limit of normal • “Non elevated” urine calcium • NB this may not be achievable – average 24-hr urine calcium in appropriately-treated patients is around 8-8.5 mmol. rPTH(1-84) therapy • Once daily injection • Achieved reduction in use of calcium and active vit D • Similar sCa and uCa levels - questionable benefit • High cost (Preotact licensed for osteoporosis, £4000 per year) Mannstadt et al, Lancet 2013, 1, 275-283..
Pseudohypoparathyroidism PTH inaction – defect downstream of PTH receptor Type 1a Type 1b Pseudopseudo Transmission Maternal. GNAS1 mutation. Loss of function in G-protein. Methylation. Mostly sporadic, or maternal. Paternal. GNAS1 mutation. Kidney PTH resistance Yes, hypocalcaemia Yes, hypocalcaemia No, normal Bone PTH resistance Yes, AHO No, hyperparathyroid bone disease Yes, AHO Other hormones Can see resistance to TSH, ADH, FSH/LH, ACTH, GHRH Maybe Treatment Activated vitamin D Activated vitamin D Parathyroidectomy
Pseudohypoparathyroidism 1b RN, diagnosed age 27 • Presents with knee pain • X-ray shows cystic changes in bones • (Diagnosis not considered by ortho) • Later… • sCa 1.37 • sPO4 1.67 • PTH 76 • Vit D normal
Pseudohypoparathyroidism 1b RN - Treatment • Alfacalcidol to normalise PTH • PTH came down to 2 • Calcium up to 2.3-2.9 • Creatinine later up 60 to 114 • USS - nephrocalcinosis • Alfacalcidol reduced • Creatinine down to 70 • Calcium 2.0-2.3 • PTH 25-30 • Urine calcium 2.4 mmol/24h • X-ray stable • Observe • Consider parathyroidectomy

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Calcium metabolism handout

  • 1.
    Calcium disorders Roderick Warren Registrarteaching Buckfastleigh, July 2014
  • 2.
    Calcium homeostasis Please seethe handout (assuming I remembered it)
  • 3.
    Vitamin D from skinand diet 25-hydroxylase 25(OH)-D – inactive (?) 1-OHase PTH effects on the kidney 1.Stimulates activation of vit D. 2.Promotes phosphate excretion. 3.Reduces calcium resorption. 1,25(OH)2-D effects on kidney Increases Ca resorption 1α-hydroxylation Stimulated by Inhibited by PTH 1,25(OH)2-D Low PO4 High PO4 PTH effect on bone Calcium export PTH production Main stimulus is low Ca2+. Inhibited by 1,25(OH)2-D. Mg required. Calcitonin production Main stimulus high Ca2+ (ionized>1.15) – also glucagon, gastrin, ß-adrenergic agonists (?reason for low Ca in acute illness) Calcitonin effects on bone • inhibits osteoclast resorption • thereby lowers Ca and PO4 • no effect on Mg 1,25(OH)2-D effects on gut Increases Ca2+ and PO4 absorption Vit D direct effect on bone? Unclear Parathyroid hormone Calcitonin 1,25-OH2-D
  • 4.
  • 5.
    Question Sue has this: •Calcium 3.4 mmol/L • PTH 0.6 pmol/l (1.6-6.9) What are the differential diagnoses?
  • 6.
    Answer Sue has this: •Calcium 3.4 mmol/L • PTH 0.6 pmol/l (1.6-6.9) Diagnosis could include: • Cancer • Vit D poisoning • Granulomatous disease etc
  • 7.
    Causes of hypercalcaemia Malignancy90% of Primary hyperparathyroidism all cases Other causes Familial Drugs: lithium, thiazides, activated vitamin D Granulomatous diseases: sarcoid etc Milk alkali syndrome Hyperthyroidism Prolonged immobilisation
  • 8.
    Malignancy causing hypercalcaemia Cancersite Mechanism Lung PTH-rp (80%) Breast Bony mets (20%) Haematological e.g. myeloma Head and neck Renal Prostate Unknown GI
  • 9.
    PTH-related peptide Fetal equivalentof PTH Maintains fetal sCa slightly higher than maternal Activates PTH receptor Typical pattern is - high calcium - low phosphate High phosphate suggests non PTH/PTHrp cause
  • 10.
    Is this hypercalcaemiadue to cancer? Low PTH - Cancer until proven otherwise: - Serum electrophoresis, Bence Jones - Tumour markers (PSA etc) - CT TAP - Bone scan - Endoscopy Normal or high PTH - Almost certainly not cancer - rarely tumours co-secrete PTH and PTH-rp - parathyroid carcinoma
  • 11.
    Question Bob has this: •Calcium 2.9 mmol/L • Phosphate 2.4 mmol/L • PTH 42 pmol/l (1.6-6.9) What are the differential diagnoses?
  • 12.
    Answer Bob has this: •Calcium 2.9 mmol/L • Phosphate 2.4 mmol/L • PTH 42 pmol/l (1.6-6.9) Diagnosis could include: • CKD with tertiary hyperparathyroidism
  • 13.
    Hyperparathyroidism Primary Secondary Parathyroid adenomaRenal failure Impaired PO4 excretion High PTH Impaired Vit D activation High calcium High PTH Low phosphate Normal or high phosphate Normal or low calcium
  • 14.
    Hyperparathyroidism Primary Secondary Parathyroid adenomaRenal failure Impaired PO4 excretion High PTH Impaired Vit D activation High calcium High PTH Low phosphate Normal or high phosphate Normal or low calcium
  • 15.
    Vitamin D from skinand diet 25-hydroxylase 25(OH)-D – inactive (?) 1-OHase PTH effects on the kidney 1.Stimulates activation of vit D. 2.Promotes phosphate excretion. 3.Reduces calcium resorption. 1,25(OH)2-D effects on kidney Increases Ca resorption 1α-hydroxylation Stimulated by Inhibited by PTH 1,25(OH)2-D Low PO4 High PO4 PTH effect on bone Calcium export PTH production Main stimulus is low Ca2+. Inhibited by 1,25(OH)2-D. Mg required. Calcitonin production Main stimulus high Ca2+ (ionized>1.15) – also glucagon, gastrin, ß-adrenergic agonists (?reason for low Ca in acute illness) Calcitonin effects on bone • inhibits osteoclast resorption • thereby lowers Ca and PO4 • no effect on Mg 1,25(OH)2-D effects on gut Increases Ca2+ and PO4 absorption Vit D direct effect on bone? Unclear Parathyroid hormone Calcitonin 1,25-OH2-D
  • 16.
    1y hyperparathyroidism -epidemiology Age Increases with age 90% aged over 50 Gender Female preponderance 70-80%
  • 17.
    1y hyperparathyroidism -epidemiology Prevalence Increasing Tayside 6 per 1000 population. About 20 per 1000 in women age >50. (Defined as Ca>2.55). Mirrors increased calcium testing. (Calcium testing increased from 5% to 15% of population each year). California About 4 per 1000 in older women (Defined as Ca>2.6.) Yu et al, Clin Endo 2009, 71, 485-493. Yeh et al, JCEM 2013, 98, 1122-1129.
  • 18.
    1y hyperparathyroidism -epidemiology How common is it really? In older women – 0.5 to 2% prevalence Based on 15% of population having blood tests What would it be if 100% of population were tested?
  • 19.
    1y hyperparathyroidism -diagnosis Elevated calcium Elevated or non-low PTH Not secondary to renal failure High phosphate eGFR<60
  • 20.
    Question Mary has this: •Calcium 2.75 mmol/L • PTH 18.2 pmol/L What are the differential diagnoses?
  • 21.
    Answer Mary has this: •Calcium 2.75 mmol/L • PTH 8.2 pmol/L • Vitamin D 15 nmol/L Diagnosis could include: • Primary hyperparathyroidism with vit D deficiency • Familial hypercalcaemia with vit D deficiency
  • 22.
    1y hyperparathyroidism -diagnosis Elevated calcium Elevated or non-low PTH Not secondary to renal failure High phosphate eGFR<60 Not due to drugs Thiazides Lithium Not due to vitamin D deficiency
  • 23.
    Effect of vitaminD on PTH Vitamin D insufficiency causes secondary hyperparathyroidism PTH on Y-axis is approx 2- 11 pmol/L Vit D on X-axis is approx 0 to >75 nmol/L
  • 24.
    Vitamin D from skinand diet 25-hydroxylase 25(OH)-D – inactive (?) 1-OHase PTH effects on the kidney 1.Stimulates activation of vit D. 2.Promotes phosphate excretion. 3.Reduces calcium resorption. 1,25(OH)2-D effects on kidney Increases Ca resorption 1α-hydroxylation Stimulated by Inhibited by PTH 1,25(OH)2-D Low PO4 High PO4 PTH effect on bone Calcium export PTH production Main stimulus is low Ca2+. Inhibited by 1,25(OH)2-D. Mg required. Calcitonin production Main stimulus high Ca2+ (ionized>1.15) – also glucagon, gastrin, ß-adrenergic agonists (?reason for low Ca in acute illness) Calcitonin effects on bone • inhibits osteoclast resorption • thereby lowers Ca and PO4 • no effect on Mg 1,25(OH)2-D effects on gut Increases Ca2+ and PO4 absorption Vit D direct effect on bone? Unclear Parathyroid hormone Calcitonin 1,25-OH2-D
  • 25.
    How could vitaminD deficiency be relevant in a hypercalcaemic patient? Theoretically (and, very occasionally, for real): • PTH is too high for FHH • Vit D replacement lowers PTH • PTH now plausible for FHH
  • 26.
    Is vitamin Dreplacement safe in primary hyperparathyroidism? Wagner Das Tucci Grey N 35 16 56 21 Vit D baseline 36 29 36.4 28 Vit D final 105 71.8 88.6 77 Calcium baseline 2.69 2.75 2.74 2.70 Calcium final 2.60 2.65 2.73 2.69 PTH baseline Unchanged 18.6 15.3 12.4 PTH final 18.0 14.1 9.2 Problem patients None None None None Wagner Endocr Pract 2013, 19(3), 420-5. Das, Endocr Abstr 2014, 34, P6. Tucci EJE 2009, 161, 189. Grey, JCEM 2005 90(4) 2122. Local anecdotal reports of hypercalcaemia. Could this be due to natural variation? CV around 4% i.e. not unusual to see +/- 0.2 mmol/L.
  • 27.
    Parathyroid bone disease Osteoporosis •Decreased BMD in PHPT patients • Rate of bone less similar to normal population Fracture • 1.5-fold increase in all fractures PHPT • 3-fold vertebra • 2-fold forearm • 1.5-fold hip
  • 28.
    Parathyroid bone disease Left– sub-periosteal erosions Above – bands of osteosclerosis “rugby jersey” appearance Right – above, metaphyseal erosion in adolescence, and below, after vit D treatment Cundy, Ulst Med J 1985, 54, S34-43
  • 29.
  • 30.
    Primary hyperparathyroidism Investigations Bloods Calcium (high). Phosphate(low or low-normal). PTH (high or normal). Liver (alk phos often high but not diagnostic). Vitamin D (usually low and very occasionally confounds diagnosis). Urine 24-hour urine calcium indices (see later). Renal USS Only in patients with history suggestive of stones. DEXA May influence surgery, or prompt bisphosphonate treatment.
  • 31.
    Question Jemima has this: •Age 79 • No symptoms • Calcium 2.71 mmol/L • PTH 7.2 pmol/L • Vit D 50 nmol/L • 24-hr urine Ca 6.8 mmol • eGFR 51 • DEXA T -2.7 Z -0.2 at spine What treatment?
  • 32.
    Answer Jemima has this:What treatment? • Age 79 Looks like PHPT • No symptoms Osteoporosis • Calcium 2.71 mmol/L • PTH 7.2 pmol/L • Vit D 50 nmol/L Really not keen on surgery • 24-hr urine Ca 6.8 mmol “Why do I need an op doc?” • eGFR 51 • DEXA T -2.7 Z -0.2 at spine
  • 33.
    Primary hyperparathyroidism Guidelines -when to operate Serum calcium > 2.80 mmol/L (Actually >0.25 mmol/L above reference range). Osteoporosis BMD T-score <-2.5 at any site, or previous fragility fracture. Renal stones Age <50 Bilzekian et al, J Clin Endo Metab 2009, 94, 335-339.
  • 34.
    Primary hyperparathyroidism Reasons tooperate Symptoms Nausea. Thirst. Fatigue. Aches. Constipation. Progressive hypercalcaemia Risk of future symptoms or hospital admission. Osteoporosis Renal stones Cardiovascular disease??
  • 35.
    Primary hyperparathyroidism Reasons notto operate Symptoms Vague. Conflicting evidence of benefit. Progressive hypercalcaemia Rare in prospective studies - less than 5%. Osteoporosis Often criteria met solely due to age. No proof of fracture reduction. Similar BMD benefit to bisphosphonates. Estimated absolute benefit is low - around 1:100 or less Too much medicine? Prevalence tripled in 10 years as a result of more blood tests.
  • 36.
    Primary hyperparathyroidism Non-surgical treatments VitaminD Not evidenced, sounds plausible. Bisphosphonates Good evidence for # prevention though not tested in PHPT. Can lower sCa slightly – would not use for this purpose. Cinacalcet Now licensed for PHPT where parathyroidectomy is inappropriate Cost £125-350 per month Lowers sCa by 0.25-0.3 mmol/L (perhaps more in more severe cases) No benefit on BMD demonstrated
  • 37.
    Surgery for “asymptomatic” hyperparathyroidism- 1 Location Sweden, Norway, Denmark. Subjects 191 patients with PHPT No parathyroid bone disease Calcium 2.6-2.85 No previous neck surgery Age 50-80 No renal impairment (creat>130) No interfering meds (thiazides etc) No kidney stones No MEN/familial hypercalcaemia No psych disorders Intervention Surgery or observation Follow-up 2 years Bollerslev et al, J Clin Endo Metab 2007, 92, 1687-1692.
  • 38.
    Outcomes Bollerslev et al,J Clin Endo Metab 2007, 92, 1687-1692. Surgery Observation N 96 95 Age 64 64 Female/male 83/13 82/13 Baseline calcium 2.70 2.69 Calcium change -0.30 -0.02 Baseline creatinine 82 81 Final creatinine 0 0 BMD lumbar 1.09 1.06 BMD change +0.04 -0.04 Fractures Not reported
  • 39.
    Outcomes Physical component of SF36– fell in both groups, no difference between groups. Mental component of SF36 – fell in both groups, no difference between groups.
  • 40.
    Surgery for “asymptomatic” hyperparathyroidism- 2 Ambrogini et al, J Clin Endo Metab 2007, 92, 1687-1692. Location Italy. Subjects 50 patients with PHPT No parathyroid bone disease Calcium 2.55-2.8 No kidney stones 24-hr urine calcium<10mmol No osteoporosis Age 50-75 No neck surgery No recent menopause No MEN/familial hypercalcaemia No major renal impairment Intervention Follow-up Surgery or observation 1 year
  • 41.
    Outcomes Bollerslev et al,J Clin Endo Metab 2007, 92, 1687-1692. Surgery Observation N 24 26 Age 64 65 Female/male 22/2 24/2 Baseline calcium 2.55 2.55 Calcium change “Normalised” +0.05 Baseline creatinine clearance 93 93 Final creatinine clearance “Stable” 98 BMD lumbar 0.85 0.83 BMD change +4% -1% Fractures Not reported
  • 42.
    Outcomes Solid line –surgery Dashed line - observation
  • 43.
    Natural history ofuntreated PHPT No really good long-term studies. Surgery vs observation trials (as before) Bollerslev (Swedish study) - tiny drop -0.02 over 2 years Ambrogini (Italian study) - small rise +0.05 over 1 year
  • 44.
    Natural history ofuntreated PHPT PEARS study – parathyroid epidemiology and audit research study, Dundee Records linkage – lab data to hospital records Definition of PHPT • Serum calcium >2.55 x 2 with PTH>3 (ref 1-6.9) • Serum calcium >2.55 x 1 with PTH>6.9 Definition of progression • Serum calcium 2.90 • Serum calcium rise of 0.2 mmol/L Yu et al, Q J Med 2011, 104, 513-521.
  • 45.
    Natural history ofuntreated PHPT Mean calcium clearly fell Individual progression • 13% of total showed any. • 1% of total showed sustained progression. Possible problems • Was it really hyperpara? • Does it apply to more severe hyperpara? Yu et al, Q J Med 2011, 104, 513-521.
  • 46.
    Osteoporosis http://www.iofbonehealth.org/epidemiology. http://www.cdc.gov/nchs/data/nhanes/databriefs/osteoporosis.pdf . Bothaccessed 27th June 2014. Prevalence increases with age • 30% of post-menopausal women in Europe have osteoporosis. • 87% of US women aged over 80 have osteopenia or osteoporosis
  • 47.
    Fracture reduction No RCTevidence for fracture reduction Retrospective studies • Fewer fractures in surgically- versus medically-treated • But obvious confounders Non-surgically treated were older and frailer What about BMD? • RCT evidence shows 5-8% benefit after surgery • What does that mean?
  • 48.
    Fracture risk estimation NoRCT evidence for fracture reduction Retrospective studies • Fewer fractures in surgically- versus medically-treated • But obvious confounders Non-surgically treated were older and frailer What about BMD? • RCT evidence shows 5-8% benefit after surgery • What does that mean?
  • 51.
    Primary hyperparathyroidism Reasons notto treat Symptoms Vague. Conflicting evidence of benefit. Progressive hypercalcaemia Rare. Osteoporosis Criteria met solely due to age. No proof of fracture reduction. Similar BMD benefit to bisphosphonates. Estimated benefit is low - around 1% absolute risk reduction. Too much medicine? Prevalence tripled in 10 years as a result of more blood tests. What treatment?
  • 52.
    Primary hyperparathyroidism Investigations Bloods Calcium (high). Phosphate(low or low-normal). PTH (high or normal). Liver (alk phos often high but not diagnostic). Vitamin D (usually low and very occasionally confounds diagnosis). Urine 24-hour urine calcium indices (see later). Renal USS Only in patients with history suggestive of stones. DEXA May influence surgery, or prompt bisphosphonate treatment.
  • 53.
    Question Roberta has this:Treatment: • Age 69 Keen to have surgery • Polyuria, fatigue, aches No contra-indications • Calcium 2.81 mmol/L • PTH 7.2 pmol/L SestaMIBI scan: • Vit D 50 nmol/L No apparent adenoma • 24-hr urine Ca 6.8 mmol • eGFR 51 What next? • DEXA T -2.7 Z -0.2 at spine
  • 54.
    Answer Roberta has this:Treatment: • Age 69 Keen to have surgery • Polyuria, fatigue, aches No contra-indications • Calcium 2.81 mmol/L • PTH 7.2 pmol/L SestaMIBI scan: • Vit D 50 nmol/L No apparent adenoma • 24-hr urine Ca 6.8 mmol • eGFR 51 What next? • DEXA T -2.7 Z -0.2 at spine Operate Or further localisation studies
  • 55.
    Primary hyperparathyroidism Localisation studies Whatis the aim? • Exclude retrosternal/ectopic adenoma • Identify solitary parathyroid adenoma vs multiple adenomata vs hyperplasia • Least possible surgery
  • 56.
    Primary hyperparathyroidism Localisation studies Conventional(Kochers) incision • Originally 8-10cm • Eventually reduced to 4-6cm Minimal access • Arbitrary definition • E.g. below 2.5cm
  • 57.
    Primary hyperparathyroidism MIBI scan Theoretically: •90% sensitivity, 98% specificity • 87% are solitary adenomas • 9% hyperplasia • 3% multiple adenomas • <1% cancer • Therefore, 78% of patients (90% of 87%) are candidates for unilateral neck exploration Reality: • Often do not localise • Equipment dependent • Affected by MNG
  • 58.
    Parathyroid surgery Exeter Parathyroid SestaMIBI Lateralising Withno pointers to secondary hyperpara Not lateralising (appropriate PTH, PO4, eGFR) Or possibility of secondary hyperpara Unilateral neck exploration Examination of both parathyroids Bilateral exploration One abnormal Both abnormal Remove and close
  • 59.
    Primary hyperparathyroidism Other localisationstudies Ultrasound Sesta-MIBI - SPECT/CT Parathyroid venous sampling Minimally-invasive radioguided parathyroidectomy (MIRP) (MIBI injection, Geiger counter to find active parathyroids) Intra-operative PTH
  • 60.
    Post-op hypocalcaemia Frequency • About10-30% of cases • More likely with… severe hypercalcaemia vitamin D deficiency very high PTH multi-gland surgery Prevention • Vitamin D repletion • Cinacalcet? • Bisphosphonates?
  • 61.
    Post-op hypocalcaemia Post-operative monitoring Checkcorrected calcium 1st post-op day Ca >2.2 Ca 2.0 – 2.19 and/or more than 0.2 mmol/l lower than pre-op Ca 1.7 – 1.99 * Ca <1.7 *or markedly symptomatic Low risk group Repeat Ca day 7 High risk group Repeat day 3-4 and day 7 Start or Continue pre-op Adcal D3 Repeat in 2 days Start 1alpha calcidol 1mcg od and Sandocal 1000 bd Give iv calcium gluconate 10ml. Repeat serum calcium after 6 hours. Commence 1 alpha calcidol 2 mcg od and Sandocal 1000 bd Ca 2.0 – 2.19 Repeat after 3 days If Ca >2.0 repeat day 7 Review 6 weeks by Endocrinology service Ca 1.7 – 1.99 Increase 1 alpha to 2mcg od. Repeat daily until Ca >2.0 Ca >2.2 Rob Dyer – draft, 2012.
  • 62.
    Question Jake has this:What investigations? • Age 39 • Polyuria, fatigue, aches • Calcium 2.85 mmol/L • PTH 78.2 pmol/L • Vit D 52 nmol/L • 24-hr urine Ca 6.8 mmol • eGFR >90 • DEXA T -0.4 • Surgery shows four-gland hyperplasia
  • 63.
    Answer Jake has this:What investigations? • Age 39 • Polyuria, fatigue, aches MEN guidelines 2012 • Calcium 2.85 mmol/L 2+ MEN-associated tumours • PTH 78.2 pmol/L 1st deg rel of known MEN1 • Vit D 52 nmol/L Parathyroid adenomas <30 • 24-hr urine Ca 6.8 mmol Multigland parathyroid disease • eGFR >90 Gastinoma • DEXA T -0.4 Pancreatic NET • Surgery shows four- gland hyperplasia
  • 64.
    Prevalence of MENin hyperparathyroidism High penetrance (95%+) of PHPT in known MEN by age 50 • Often said no need to consider MEN if diagnosed over 50 But would PHPT be diagnosed before 50 if MEN not known? • E.g. develops age 45, diagnosed age 55? Prevalence of MEN in PHPT • Uchino et al – 25% menin mutations • Yip et al – 4% prevalence but 26% if hyperplasia • De Laat et al – 7% prevalence Always ask about FH of hypercalcaemia, renal stones, brain tumours, neck surgery, ulcers, pancreatic tumours
  • 65.
    Primary vs secondaryvs tertiary hyperparathyroidism Divide calcium by 4 to get mmol/L DividePTHbyabout10togetpmol/L
  • 66.
    Primary Secondary Parathyroid adenomaRenal failure Impaired PO4 excretion High PTH Impaired Vit D activation High calcium High PTH Low phosphate Normal or high phosphate Normal or low calcium Secondary hyperparathyroidism
  • 67.
    Secondary hyperparathyroidism High ornormal phosphate Low or normal calcium High PTH eGFR below 60 Levin–AmJKidDis1991,34,125-134.
  • 68.
    NICE 2008 guidelines •Monitor in CKD 4/5 (e.g. in diabetes clinics) • Measure Ca, PO4, PTH • Decide frequency of monitoring by results and clinical circumstances. Seek specialist opinion. (Just do it annually?). • Cholecalciferol or ergocalciferol for CKD 1-3b • Alfacalcidol or calcitriol for CKD 4-5 Secondary hyperparathyroidism management
  • 69.
    AKA refractory secondaryhyperparathyroidism • Development of autonomous nodular parathyroid hyperplasia • Hypercalcaemia Indications for surgery • Severe hypercalcaemia/hyperphosphataemia • Parathyroid bone disease • Extraskeletal calcification • Unexplained symptomatic myopathy • WITH PTH>800 pg/mL (88 pmol/L) (all of the above can develop in dialysis patients for other reasons, so must confirm presence of hyperparathyroidism) “Tertiary” hyperparathyroidism
  • 70.
    Surgical options –no agreement which is best • Total parathyroidectomy (unpopular) • Total parathyroidectomy with auto-transplantation into forearm Theoretically – if recurrent, no need for re-exploration of neck. But persistent hypercalcaemia after removal of arm graft is quite common, i.e. it was in the neck all along. • Subtotal parathyroidectomy (leaving 40-60mg of the least hyperplastic gland) “Tertiary” hyperparathyroidism
  • 71.
    Persistent hyperparathyroidism • Nodularhyperplasia from prolonged secondary hyperpara Normal renal function • Eliminates resistance to PTH due to uraemia • Restores normal 1-hydroxylation of vit D Hypercalcaemia after renal transplant
  • 72.
    Causes of hypercalcaemia Malignancy90% of Primary hyperparathyroidism all cases Other causes Familial Drugs: lithium, thiazides, activated vitamin D Granulomatous diseases: sarcoid etc Milk alkali syndrome Hyperthyroidism Prolonged immobilisation
  • 73.
    Familial benign (hypocalciuric) hypercalcaemia CaSRmutation • Body “sees” a high calcium level as normal • Present from birth • One explanation for failed parathyroid surgery Misnamed • Normocalciuric (just lower than expected) In most cases: • PTH not very high • Urine calcium not elevated • Calcium:creatinine clearance ratio <0.02 • No osteoporosis • Asymptomatic
  • 74.
    Familial (benign) (hypocalciuric) hypercalcaemia PHPTFBHH PTH pmol/L 50% above 8-9 50% below 3 95% below 8.5 99% below 9.1 24-hr urine calcium mmol 70% above 6.5 50% below 2.3 95% below 6.5 99% below 9.0 Calcium:creatinine clearance ratio 98% below 0.02 65% above 0.02 95% above 0.06 Gunn et al Ann Clin Biochem 2004, 41, 441-458 Christensen et al Clin Endo 2008, 69, 713-720. CCCR>0.02 excludes FHH. Consider genetic testing if <0.02 (NB only 70% of familial cases are positive on genetic tests).
  • 75.
    Familial benign (hypocalciuric) hypercalcaemia Severecases are reported • Homozygous mutations • Severe symptomatic hypercalcaemia • Osteoporosis • Very high PTH
  • 76.
    Parathyroid jaw tumoursyndrome • Rare • Autosomal dominant • Parathyroid tumours ~15% carcinomas • Fibro-osseous tumours of jaw bones • Plus loads of other tumours – Wilm’s, renal cysts, renal hamartomas, renal cortical adenomas, papillary renal cell carcinomas, pancreatic adenocarcinomas, testicular seminomas, uterine.
  • 77.
    Lithium Causes hyperparathyroidism Expect PTHto be elevated. If low PTH - look for cancer. Also causes diabetes insipidus Severe hypercalcaemia causes dehydration. DI causes dehydration. Dehydration worsens hypercalcaemia. Nightmare combo Mania with severe hypercalcaemia and renal impairment.
  • 78.
    Lithium – prevalenceof hypercalcaemia Lally et al 5% of 33 patients Twigt et al 15.6% of 314 patients Duration of Li therapy was main predictor No hypercalcaemia in control group of non-Li psych patients Bendz et al 6% incidence in 142 patients over 19 years 13 consented to trial of Li withdrawal – all ineffective Ir Med J 2013 106 15-17. Int J Bipolar Dis 2013 1 18. J Int Med 1996 240 357-365.
  • 79.
    Lithium – managementof hyperparathyroidism Surgery Adenoma vs hyperplasia Withdrawal of lithium Mainly ineffective (short-term studies only) But worth a try
  • 80.
    Thiazides Effects ● Small increase(1-2%) in serum total calcium ● Small increase (10-20%) in PTH ● Little or no effect on ionized calcium ● Reduction in urinary calcium excretion Does it matter? ● Probably not ● Most cases of hypercalcaemia with thiazides turn out to be coincidental primary hyperparathyroidism Rejnmark et al. Euro J Clin Invest 2003, 33, 41-50. Wermers et al, Am J Med 2007, 120, 911.
  • 81.
    Thiazides and hypercalcaemia– practical points Stop the thiazide ● Recheck calcium and PTH ● Is there malignancy? ● Is there primary hyperparathyroidism? Could restart it if all OK ● E.g. if mild primary hyperpara for “watch and wait”
  • 82.
    No cause found.What next? Hypercalcaemia Low or non-elevated PTH No evidence of malignancy No lithium No thiazides No calcium/vit D supplements Normal thyroid function
  • 83.
    Rarer stuff Granulomatous diseases:sarcoid etc CT chest. s-ACE?? Milk alkali syndrome Prolonged immobilisation Cirrhosis I don’t know the mechanism Adrenal insufficiency I don’t know the mechanism Primary or secondary
  • 84.
    Acute management ofhypercalcaemia When is admission required? • Definitely if sCa>3.5 mmol/L • 3-3.5 mmol/L – depends on trend, age, frailty, renal function etc
  • 85.
    Acute management ofhypercalcaemia 1. Hydration • 4-6 litres 0.9% saline over 24 hours • Loop diuretics for fluid overload – not effective at lowering calcium 2. IV bisphosphonate • Zoledronate 4mg • Pamidronate 30-90mg 3. Alternatives • Prednisolone 40mg (inhibits 1,25-D production – useful in granuloma, lymphoma, 25-D intoxication) • Cinacalcet • Calcitonin Society for Endocrinology 2013 guideline
  • 89.
  • 90.
    Causes of hypocalcaemia EDTAcontamination Low magnesium Respiratory alkalosis PPI Vit D deficiency Hypoparathyroidism - primary - post-surgical - pseudo
  • 91.
    EDTA contamination EDTA leakageinto biochem tube causes... High potassium Low calcium, magnesium, alk phos Fill biochem tubes before haematology tubes
  • 92.
    Hypocalcaemia due to hypomagnesaemia Lowmagnesium is common in… ● elderly ● diarrhoea ● diuretics ● patients taking PPIs Treatment ● stop diuretics ● stop PPIs ● oral magnesium supplements (limited efficicacy) ○ Maalox or Mucogel - 35 mL/day in divided doses ○ magnesium glycerophosphate - 4 tabs per day ● IV replacement
  • 93.
    What level ofhypomagnesaemia requires treatment? When you write a guideline, it always ends up more cautious than your real practice ● Many guidelines say Mg<0.5 mmol/L requires urgent IV treatment My comments ● Hypomagnesaemia seems common in general medical patients ● It definitely is common in frail elderly ● In 169 long-term geriatric care patients, 53% had sMg<0.45 mmol/L, 18% had sMg<0.35 mmol/L ● I would treat principally if symptomatic or hypocalcaemic or hypokalaemic Alinzon et al, Arch Geront Ger 2010, 51, 36-40.
  • 94.
    Hypocalcaemia due toalkalosis Normal ● albumen carries negative charge ● some albumen is bound to positive H+ ● some Ca2+ is bound to remaining albumen ● free/ionized Ca2+ is biologically active Hyperventilation ● respiratory alkalosis due to blowing off CO2 ● lower H+ concentration ● more negative charged albumen free to bind Ca2+ ● free/ionized Ca2+ falls ● total sCa does not change
  • 95.
    When should wemeasure ionized calcium? Ideally – always In the real world ● if you have a calcium abnormality but struggling to make a diagnosis ● if symptoms suggest hypocalcaemia but normal total sCa
  • 96.
    Hypocalcaemia due tovitamin D deficiency Seen in… ● malnutrition ● elderly ● institutionalised ● coeliac / malabsorption / short bowel Treatment ● see formulary ● Adcal D3 or Calcichew D3 (400 units per tab) ● Fultium D3 (800 units per tab) ● OTC - at least 2000 units per day, 8p per day from H&B
  • 97.
    Oral: Hypocalcaemia is rare,well under 0.5% Usually occurs after a few weeks Transient IV high dose: Hypocalcaemia more common but still rare Most cases have other risk factors: + coeliac disease + hypoparathyroidism Hypocalcaemia due to bisphosphonates
  • 98.
    Gain of functionCaSR mutation • Consider if diagnosed young, and never had normal calcium • Family history helpful. (NB affected relatives likely undiagnosed). No simple characterisation • Earliest reported cases had marked hypocalcaemia, low PTH and clearly elevated CCCR. (Perhaps that’s why they were identified). • Confirmed familial cases with no symptoms and normal CCCR. • Treat if symptomatic e.g. seizures • Many case reports of calcification of skull, brain, kidney, cataract • Treatment will increase calcium throughput Familial (hypercalciuric) hypocalcaemia
  • 99.
    Question Bill has this: •Calcium 1.4 mmol/L • PTH 76 pmol/l (1.6-6.9) What is the diagnosis?
  • 100.
    Answer Bill has this: •Calcium 1.4 mmol/L • PTH 76 pmol/l (1.6-6.9) Diagnosis could include: • Vitamin D deficiency • Renal failure • Rhabdomyolysis • Pseudohypoparathyroidism • etc
  • 101.
    Hypoparathyroidism Causes • Usually post-surgical •Rarely, primary or pseudo Features • Low calcium • High phosphate • High PTH • Vitamin D replete • Normal renal function
  • 102.
    Vitamin D from skinand diet 25-hydroxylase 25(OH)-D – inactive (?) 1-OHase PTH effects on the kidney 1.Stimulates activation of vit D. 2.Promotes phosphate excretion. 3.Reduces calcium resorption. 1,25(OH)2-D effects on kidney Increases Ca resorption 1α-hydroxylation Stimulated by Inhibited by PTH 1,25(OH)2-D Low PO4 High PO4 PTH effect on bone Calcium export PTH production Main stimulus is low Ca2+. Inhibited by 1,25(OH)2-D. Mg required. Calcitonin production Main stimulus high Ca2+ (ionized>1.15) – also glucagon, gastrin, ß-adrenergic agonists (?reason for low Ca in acute illness) Calcitonin effects on bone • inhibits osteoclast resorption • thereby lowers Ca and PO4 • no effect on Mg 1,25(OH)2-D effects on gut Increases Ca2+ and PO4 absorption Vit D direct effect on bone? Unclear Parathyroid hormone Calcitonin 1,25-OH2-D
  • 103.
    Hypoparathyroidism Lack of PTH •Kidneys don’t retain calcium • Kidneys don’t excrete phosphate Activated vitamin D treatment • Increase calcium absorption from gut • Increase phosphate absorption from gut Overall effect • Forced intestinal calcium absorption • Increased renal calcium throughput • High calcium x phosphate product • Nephrocalcinosis (and other calcifcation)
  • 104.
    Hypoparathyroidism Treatment targets • sCaaround lower limit of normal • “Non elevated” urine calcium • NB this may not be achievable – average 24-hr urine calcium in appropriately-treated patients is around 8-8.5 mmol. rPTH(1-84) therapy • Once daily injection • Achieved reduction in use of calcium and active vit D • Similar sCa and uCa levels - questionable benefit • High cost (Preotact licensed for osteoporosis, £4000 per year) Mannstadt et al, Lancet 2013, 1, 275-283..
  • 105.
    Pseudohypoparathyroidism PTH inaction –defect downstream of PTH receptor Type 1a Type 1b Pseudopseudo Transmission Maternal. GNAS1 mutation. Loss of function in G-protein. Methylation. Mostly sporadic, or maternal. Paternal. GNAS1 mutation. Kidney PTH resistance Yes, hypocalcaemia Yes, hypocalcaemia No, normal Bone PTH resistance Yes, AHO No, hyperparathyroid bone disease Yes, AHO Other hormones Can see resistance to TSH, ADH, FSH/LH, ACTH, GHRH Maybe Treatment Activated vitamin D Activated vitamin D Parathyroidectomy
  • 106.
    Pseudohypoparathyroidism 1b RN, diagnosedage 27 • Presents with knee pain • X-ray shows cystic changes in bones • (Diagnosis not considered by ortho) • Later… • sCa 1.37 • sPO4 1.67 • PTH 76 • Vit D normal
  • 107.
    Pseudohypoparathyroidism 1b RN -Treatment • Alfacalcidol to normalise PTH • PTH came down to 2 • Calcium up to 2.3-2.9 • Creatinine later up 60 to 114 • USS - nephrocalcinosis • Alfacalcidol reduced • Creatinine down to 70 • Calcium 2.0-2.3 • PTH 25-30 • Urine calcium 2.4 mmol/24h • X-ray stable • Observe • Consider parathyroidectomy